Mountains are the water towers of the world, supplying a substantial part of both natural and anthropogenic water demands1,2. They are highly sensitive and prone to climate change3,4, yet their importance and vulnerability have not been quantified at the global scale. Here, we present a global Water Tower Index, which ranks all water towers in terms of their water-supplying role and the downstream dependence of ecosystems and society. For each tower, we assess its vulnerability related to water stress, governance, hydropolitical tension and future climatic and socio-economic changes. We conclude that the most important water towers are also among the most vulnerable, and that climatic and socio-economic changes will affect them profoundly. This could negatively impact 1.9 billion people living in (0.3 billion) or directly downstream of (1.6 billion) mountain areas. Immediate action is required to safeguard the future of the world’s most important and vulnerable water towers.